VEGF controls endothelial-cell permeability by promoting the β-arrestin-dependent endocytosis of VE-cadherin

J Gavard, JS Gutkind - Nature cell biology, 2006 - nature.com
Nature cell biology, 2006nature.com
How vascular endothelial growth factor (VEGF) induces vascular permeability, its first
described function, remains poorly understood. Here, we provide evidence of a novel
signalling pathway by which VEGF stimulation promotes the rapid endocytosis of a key
endothelial cell adhesion molecule, VE-cadherin, thereby disrupting the endothelial barrier
function. This process is initiated by the activation of the small GTPase Rac by VEGFR-2
through the Src-dependent phosphorylation of Vav2, a guanine nucleotide-exchange factor …
Abstract
How vascular endothelial growth factor (VEGF) induces vascular permeability, its first described function, remains poorly understood. Here, we provide evidence of a novel signalling pathway by which VEGF stimulation promotes the rapid endocytosis of a key endothelial cell adhesion molecule, VE-cadherin, thereby disrupting the endothelial barrier function. This process is initiated by the activation of the small GTPase Rac by VEGFR-2 through the Src-dependent phosphorylation of Vav2, a guanine nucleotide-exchange factor. Rac activation, in turn, promotes the p21-activated kinase (PAK)-mediated phosphorylation of a highly conserved motif within the intracellular tail of VE-cadherin. Surprisingly, this results in the recruitment of β-arrestin2 to serine-phosphorylated VE-cadherin, thereby promoting its internalization into clathrin-coated vesicles and the consequent disassembly of intercellular junctions. Ultimately, this novel biochemical route by which VEGF promotes endothelial permeability through the β-arrestin2-dependent endocytosis of VE-cadherin may help identify new therapeutic targets for the treatment of many human diseases that are characterized by vascular leakage.
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